The proposed studies will test the hypothesis that increases in glomerular pressures and flows cause glomerular injury. This hypothesis derives from previous work by the principal investigator and others. Glomerular hemodynamics will be measured by micropuncture techniques and will be correlated with glomerular injury as assessed by histologic studies and measures of proteinuria. Two disease models will be employed. The subtotally nephrectomized rat will be used as a model of the response of remnant nephrons to the influence of secondary, or compensatory, renal hemodynamic changes. The streptozocin diabetic rat will be investigated as a model of glomerulopathy associated with primary hemodynamic alterations. The posited relationship between glomerular hemodynamics and injury would explain the mechanism of glomerulopathy in those diseases, such as diabetes, with primary hemodynamic changes. Moreover, this hypothesis would account for the clinical observation that renal failure progresses inexorably in the vast majority of patients after a wide range of initial insults. According to this theory, such progression occurs because of the adverse effects of compensatory hemodynamic alterations on remnant nephrons. Thus, after an initial loss of functioning renal mass, the relatively undamaged remnant nephrons would be destroyed by a self-perpetuating process of sclerosis driven by their own compensatory hemodynamic changes. The proposed studies will subject this hypothesis to scrutiny and at the same time will elucidate the mechanisms underlying the glomerular hemodynamic changes observed in the two disease models. Finally, these studies will assess a number of potentially therapeutic maneuvers which could prove useful not only in understanding, but also in influencing, the course of these prototypic glomerulopathies.